(1) Field of the Invention
The present invention relates generally to vaccines and, more particularly, to a method and vaccine for inducing mucosal immunity and a method for selecting the vaccine candidate.
(2) Description of the Prior Art
Both killed and live vaccines have been administered by parenteral injection to achieve systemic humoral and cellular immunity.
For mycobacteria and, in particular, Mycobacterium avium subspecies paratuberculosis (MAP), commitment to parenteral administration has been based on the relative efficacy of bacillus Calmette-Guerin (BCG) vaccine against Mycobacterium tuberculosis in human beings.
Basic similarities exist between Mycobacterium tuberculosis and Mycobacterium avium subspecies paratuberculosis. The portal of infection for M. tuberculosis is the lung; its site of pathology is the lung. For MAP, its portal of infection is the gastrointestinal tract which is also its organ of manifested disease.
What has not been computed into prior MAP vaccine development is the fact that upper lobe disease is a metastatic site of disease resulting from hematogenous dissemination. Inhalation acquisition of M. tuberculosis primarily involves the superior segments of the lower lobes or the right middle lobe of the lung. Gohn complexes occur in the lymphatic sites of the primary infection. If host T-cell mediated and humoral immunity do not arrest organismal replication at site of initial infection, the organism enters into the blood stream and seeks out optimal conditions for future replication, more specifically, metastatic progressive upper lobe disease. Upper lobe disease is the consequence of bacillemia and metastatic implantation, which accounts for the success of IgG immunoglobulins and systemic T-cell immunity in precluding or arresting the development of metastatic disease in the upper lobes.
For Mycobacterium avium subspecies paratuberculosis (MAP), the portal of infection is die gastrointestinal tract. The target organ is the gastrointestinal disease Gastrointestinal histopathology does not require a phase of systemic dissemination. Hematogenous dissemination is a late phenomena and not a major factor in determining the consequences of disease for the animal.
Mucosal local humoral immunity is mediated primarily by the IgA class of immunoglobulins. IgG specific antibodies do function in a secondary manner within mucosal immunity. What parenteral killed and live MAP vaccines have demonstrated is that IgG specific antibodies, in concert with transported T-cell response can impact locally on the magnitude of fecal shedding and systemically prolong the interim between established mucosal infection and Johne's disease. The importance of local immunity for mycobacteria is inferred by the observation that immunization of guinea pigs with vaccines directed against hsp60 of Mycobacterium tuberculosis did not preclude the development of necrotizing bronchiolitis when a hsp60 heat shock protein of M. tuberculosis was applied to the traditional portal of infection, but the animals were protected systemically.
Drawing parallels between Mycobacterium tuberculosis and MAP, it is presumed that some cows with either Phase I and II infection may self-cure. Work done in conjunction with the Department of Pathobiology at the University of Florida, College of Veterinary Medicine has suggested that self-cure may occur in cows with Phase III disease. Serial blood samples were obtained from a cow with culture and serologically documented Johne's disease in order to collect high titer antibody titered serum. Prior to euthanasia, the animal cease having diarrhea and began gaining weight. At necropsy, the gastrointestinal tract was basically normal. A rare histological section demonstrated MAP.
Disease, as opposed to infection, is often a titration between infectious inoculum, organismal virulence and host immune response. If the inoculum dose is controlled and organismal virulence is altered, it is reasonable to assume that the probability of host immunity prevailing is enhanced. With a live oral vaccine, prolonged immunological memory is more likely despite infection containment.
Attempts to induce local immunity with heat-killed vaccine strains have been unsuccessful.
The failure of both live and killed, parentally administered, MAP vaccines to preclude ultimate disease turns the focus of investigation to the importance of local immunity induction within the target organ. A need exists for a vaccine that is effective in preventing disease at the portal of infection/target organ.